1. Prior uses of MDAM, Methotrexate and the 5-Fluoropyrimidines
MDAM (4-amino-4-deoxy-.gamma.-methylene-10-deazaaminopterin), is a potent inhibitor of dihydrofolate reductase (DHFR) and is currently in clinical trials in the United States as a treatment for human solid tumors and leukemias. MDAM is described and claimed in U.S. Pat. Nos. 4,996,207; 5,073,554; and 5,260,296; and other patents, both in the United States and abroad.
MDAM is an analogue of Methotrexate (Amethopterin), a DHFR inhibitor which has been in use for many years to treat various types of human cancer and also has been prescribed as a treatment for some forms of rheumatoid arthritis, psoriasis and asthma. As described in the above listed MDAM patents, Methotrexate (MTX) undergoes polyglutamylation which can result in significant patient toxicity, particularly myelosuppression and GI toxicity.
MDAM does not undergo the polyglutamylation commonly associated with Methotrexate, and has a higher therapeutic index than MTX. Further, MDAM is not as susceptible to MDR or MRP resistance and is more effective in treating several types of drug-resistant cancers.
5-Fluoropyrimidines, particularly 5-FU (5-fluorouracil) and the like, are widely used antitumor agents which have also been used for a number of years to treat various types of human cancers. 5-FU has been used both alone and in combination with other chemotherapeutic agents, particularly with Methotrexate to treat a number of different types of tumors and leukemias. 5-FU inhibits thymidylate synthetase and other enzymes to interfere with DNA synthesis, is directly incorporated into DNA and RNA, and also blocks formation of uracil phosphatase to inhibit RNA synthesis as well.
As with MTX, the major toxic effects of 5-FU are also myelosuppression and GI toxicity, as well as other toxicities. 5-FU is also susceptible to drug resistant strains of cancers, and has a low therapeutic index if used alone.
UFT is a combination of a 5-FU prodrug (N-furan-2-yl-5-fluorouracil), and uracil in a 1:4 ratio. Capecitabine is a novel compound currently in clinical trials throughout the world, and has exhibited oral efficacy against certain tumors.
S-1 (A combination of 5-FU (or the furanyl prodrug listed above):potassium oxonate:2,4-dihydroxy-5-chloropyridine(CDHP), in a 1:1:0.4 ratio) is a recently developed antitumor agent. A study was conducted recently which compared the activity of S-1 with the activity of UFT (5-FU:Uracil, 1:4), against a common human cancer (human colorectal adenocarcinoma KM12C). Shirasaka, et al, "Antitumor Activity of 1 M Tegafur- 0.4 M 5-Chloro-2,4-dihydroxypyridine- 1 M Potassium Oxonate (S-1) against Human Colon Carcinoma Orthotopically Implanted into Nude Rats," Cancer Research, vol. 26, pg. 2602 (1996). S-1 was found to be significantly more effective against this tumor type than either 5-FU or UFT alone.
2. Combinations of Chemotherapeutic Drugs
Clinicians have consistently tried to improve the response of cancer patients by combining two or more antitumor drugs into a single therapeutic regimen. By combining two or more chemotherapeutic agents, most often with different mechanisms of action, the clinician is able to both increase the therapeutic index of the individual drugs, and at the same time reduce the toxic effects to the patient.
A relevant example (with regard to the subject matter of this invention) of combination chemotherapy has been the concurrent administration of Methotrexate and 5-FU. A number of studies have been conducted which explored the benefits (and the drawbacks) of combination therapy utilizing these two well-known drugs, and the references which disclose the results of these studies are included in the List of References, supra.
A number of other combinations have also been employed by clinicians and researchers in their efforts to treat various forms of cancer in various stages of the disease. The focus of these combination efforts is to increase the therapeutic index of the individual drugs, hopefully in a synergistic fashion, while at the same time decreasing the risk of harmful effects to the patient from the use of such drugs. In the case of Methotrexate (MTX)/5-FU combination therapy, the synergistic combination involved the pretreatment of the cancer cells with MTX, followed by a treatment with 5-FU to enhance cancer cell kill. This combination was time and sequence dependent, and deviation from the preferred schedule of treatment actually decreased the effects of the combination as compared with individual results.
The number of combination therapies which have been used to treat various forms of cancer is very large and may be found throughout the literature. This is due to the large number of tumor cell lines which have been identified, and to the ultimate goals in any treatment program-providing better quality of life, while controlling the disease with the safety of the patient foremost.